Fu Xiu-Qing, Peng Jian, Wang Ai-Hua, Luo Zhen-Ge
1School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210 China.
2State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, 200031 China.
Cell Discov. 2020 Mar 3;6:9. doi: 10.1038/s41421-020-0143-5. eCollection 2020.
During the development of mammalian neuromuscular junction (NMJ), the original supernumerary axon inputs are gradually eliminated, finally leaving each muscle fiber innervated by a single axon terminal. However, the molecular cues that mediate the elimination of redundant axon inputs remain unclear. Here we show that tumor necrosis factor-α (TNFα) expressed in postsynaptic muscle cells plays an important role in presynaptic axonal elimination at the NMJ. We found that intramuscular injection of TNFα into the levator auris longus (LAL) muscles caused disassociation of presynaptic nerve terminals from the postsynaptic acetylcholine receptor (AChR) clusters. By contrast, genetic ablation of TNFα globally or specifically in skeletal muscle cells, but not in motoneurons or Schwann cells, delayed the synaptic elimination. Moreover, ablation of TNFα in muscle cells attenuated the tendency of activity-dependent competition in a motoneuron-muscle coculture system. These results suggest a role of postsynaptic TNFα in the elimination of redundant synaptic inputs.
在哺乳动物神经肌肉接头（NMJ）发育过程中，最初多余的轴突输入会逐渐被消除，最终每条肌纤维仅由单个轴突终末支配。然而，介导消除多余轴突输入的分子信号仍不清楚。在此我们表明，突触后肌细胞中表达的肿瘤坏死因子-α（TNFα）在NMJ突触前轴突消除中起重要作用。我们发现，向耳长提肌（LAL）肌肉内注射TNFα会导致突触前神经终末与突触后乙酰胆碱受体（AChR）簇解离。相比之下，在全身或特异性地在骨骼肌细胞而非运动神经元或雪旺细胞中对TNFα进行基因敲除，会延迟突触消除。此外，在肌细胞中敲除TNFα会减弱运动神经元-肌肉共培养系统中活性依赖性竞争的趋势。这些结果表明突触后TNFα在消除多余突触输入中发挥作用。
